Epertinib

A significant hurdle in cancer treatment arises from multidrug resistance (MDR), often due to overexpression of ATP-binding cassette (ABC) transporters like ABCB1 and/or ABCG2 in cancer cells. These transporters actively diminish the efficacy of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux and reducing intracellular drug accumulation in cancer cells. Addressing multidrug-resistant cancers poses a significant challenge due to the lack of approved treatments, prompting the exploration of alternative avenues like drug repurposing (also referred to as drug repositioning) of molecularly targeted agents to reverse MDR-mediated by ABCB1 and/or ABCG2 in multidrug-resistant cancer cells. Epertinib, a potent inhibitor of EGFR and HER2 currently in clinical trials for solid tumors, was investigated for its potential to resensitize ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic agents. Our findings reveal that at sub-toxic, submicromolar concentrations, epertinib restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. The results demonstrate that epertinib enhances drug-induced apoptosis in these cancer cells by impeding the drug-efflux function of ABCB1 and ABCG2 without altering their expression. ATPase activity and molecular docking were employed to reveal potential interaction sites between epertinib and the drug-binding pockets of ABCB1 and ABCG2. In summary, our study demonstrates an additional pharmacological capability of epertinib against the activity of ABCB1 and ABCG2. These findings suggest that incorporating epertinib into combination therapy could be advantageous for a specific patient subset with tumors exhibiting high levels of ABCB1 or ABCG2, warranting further exploration.

The bacterium Bacillus coagulans has attracted interest because of its ability to produce spores and advantageous probiotic traits, such as facilitating food digestion in the intestine, managing some disorders, and controlling the symbiotic microbiota. Spore-forming probiotic bacteria are especially important in the probiotic industry compared to non-spore-forming bacteria due to their stability during production and high resistance to adverse factors such as stomach acid. When spore-forming bacteria are exposed to environmental stresses, they enter the sporulation pathway to survive. This pathway is activated by the final phosphorylation of the master regulator of spore response, Spo0A, and upon achieving the phosphorylation threshold. Spo0A is indirectly inhibited by some enzymes of the aspartate response regulator phosphatase (Rap) family, such as RapJ. RapJ is one of the most important Rap enzymes in the sporogenesis pathway, which is naturally inhibited by the pentapeptides.

This study used structure-based virtual screening and molecular dynamics (MD) simulation studies to find potential RapJ hits that could induce the sporulation pathway. The crystal structures of RapJ complexed with pentapeptide clearly elucidated their interactions with the enzyme active site.

Based on the binding compartment, through molecular docking, MD simulation, hydrogen bonds, and binding-free energy calculations, a series of novel hits against RapJ named tandutinib, infigratinib, sitravatinib, linifanib, epertinib, surufatinib, and acarbose were identified. Among these compounds, acarbose obtained the highest score, especially in terms of the number of hydrogen bonds, which plays a major role in stabilizing RapJ-ligand complexes, and also according to the occupancy percentages of hydrogen bonds, its hydrogen bonds were more stable during the simulation time. Consequently, acarbose is probably the most suitable hit for RapJ enzyme. Notably, experimental validation is crucial to confirm the effectiveness of the selected ligands.